Liver-directed cell therapy has siginificant potential for many disorders. Studies of hepatocyte transplantation provided insights into cell therapy, as well as novel models for basic studies concerning liver regeneration and stem cell biology. We now wish to define the potential of additional liver cell types, especially endothelial cells, which constitute a major liver cell compartment and contribute in cell-cell signaling, coagulation factor synthesis and immunological responses. Our major hypothesis is that sinusoidal liver endothelial cells will engraft and proliferate in the liver of suitable recipients. Insights into these properties of liver endothelial cells will offer ways to treat specific disorders and to modulate the behavior of other liver cell types for various applications. Therefore, we propose to conduct studies in mice for establishing mechanisms concerning the survival, fate and function of transplanted endothelial cells. Our specific objectives are to first establish the efficiency with which transgenically marked endothelial cells will engraft in the liver of congeneic recipients, including after the introduction of reporter genes with viral vectors, and demonstrate specific mechanisms that would facilitate engraftment and/or proliferation of transplanted endothelial cells. We will then examine whether therapeutic genes can be successfully expressed in transplanted endothelial cells and whether the natural history of hepatic disease processes could be altered by such manipulations. Furthermore, we will examine whether cell-cell interactions can be reproduced in the in vivo setting, such that engraftment of transplanted mouse or human hepatocytes could be modulated in immunodeficient animals by cotransplantation of endothelial cells. Also, we will examine whether transplantation of unperturbed or genetically modified endothelial liver cells and transplantation of endothelial stem/progenitor cells could help ameliorate disease in mice. We expect that these studies will generate insights into endothelial cell biology, offer novel biological models and help define the therapeutic potential of liver endothelial cells.